Guanidine derivatives

ABSTRACT

This invention relates to new heterocyclic derivatives of guanidine and more particularly to such derivatives which have hypoglycemic activity, their methods of use for treating hyperglycemia and novel intermediate compounds for their preparation.

This is a division, of application Ser. No. 07/921,543, filed Jul. 28,1992, which is hereby incorporated by reference pending.

FIELD OF THE INVENTION

This invention relates to new heterocyclic derivatives of guanidine andmore particularly to such derivatives which have hypoglycemic activity.

BACKGROUND OF THE INVENTION

Treatment of non-insulin dependent diabetes mellitus (NIDDM) andhyperglycemia associated therewith is directed towards restoringnomaglycemia by improving insulin secretion and reducing insulinresistance. Reduction of blood glucose currently relies on diet andweight control, oral hypoglycemic agents (notably sulfonylureas andbiguanides), and insulin. While this triad of therapeutic approaches mayprovide the desired benefits on a short-term basis, substantial numbersof patients often fail on diet and sulfonylureas, resulting ininadequate glycemic control. Therefore, newer therapeutic agents areneeded which can provide greater effectiveness in the treatment ofNIDDM.

Linogliride (U.S. Pat. No. 4,211,867), is an effective hypoglycemicagent, whose structure is depicted below: ##STR1## It is an object ofthe present invention to prepare novel hypoglycemic agents with equal orbetter efficacy than linogliride for treating hyperglycemia. Additionalobjects and advantages of the invention will be set forth, in part, inthe description which follows and in part will be obvious from thisdescription, or may be learned by practice of the invention. The objectsand advantages of this invention are realized and obtained by means ofthe compositions, methods and the combinations particularly pointed outin the appended claims.

SUMMARY OF THE INVENTION

To achieve the objects in accordance with the purposes of the invention,as embodied and fully described herein the present invention is directedto new heterocyclic derivatives of guanidine which exhibit hypoglycemicactivity having the formula I: ##STR2## wherein: R is selected from thegroup consisting of H, alkyl (C₁ -C₈), branched alkyl (C₃ -C₅),cycloalkyl (C₃ -C₇), aryl (preferably naphthyl or phenyl and morepreferably phenyl) and aralkyl wherein the aryl portion is preferablyphenyl or naphthyl and the alkyl portion is preferably C₁ -C₅ ;

R₁ and R₂ are selected from the group consisting of hydrogen, alkyl (C₁-C₅), branched alkyl (C₃ -C₅), cycloalkyl (C₃ -C₇), aralkyl wherein thealkyl portion is C₁ -C₅, hydroxyalkyl wherein the aryl portion is phenylor substituted phenyl wherein the substituents are selected from alkyl(C₁ -C₅), alkoxy (C₁ -C₄) and halogen such as Br, F or Cl, or R₁ R₂ Nmay be taken together to form a heterocyclic ring containing 3-5 carbonatoms where said ring may contain N and one or more (preferably 1-3)heteroatoms such as O or S;

R₃ is selected from the group consisting of hydrogen alkyl (C₁ -C₅),alkoxy (C₁ -C₄) and halogen such as Br, F or Cl, preferably R₃ ismethyl, methoxy or F;

R₄ and R₅ are the same or different and are selected from the groupconsisting of alkyl (C₁ -C₅), branched alkyl (C₃ -C₅), cyclohexyl,cyclopentyl or R₄ R₅ N may be taken together to form a heterocyclic ringcontaining 3-5 carbon atoms where said ring may contain N and one ormore (preferably 1-3) heteroatoms such as O,N or S to form heterocyclicrings preferably piperidino, morpholino, pyrrolidino and thiomorpholino,particularly morpholino.

The present invention is not restricted to the stereoisomerconfiguration depicted by Formula I but also includes otherstereoisomers and tautomers of I which may exist. The present inventionfurther includes pharmaceutically acceptable salts of theabove-described compounds.

As embodied and described herein, the invention further comprisesmethods of treating hyperglycemia comprising the steps of administeringa therapeutically or blood glucose lowering effective amount of one ormore hypoglycemic agents of Formula I to a patient suffering from ahyperglycemic condition. Effective dosage amounts will vary inaccordance with particular circumstances relating to the patient andcondition being treated as would be determined by those skilled in theart.

As embodied and described herein, the invention further comprises novelintermediate compounds for preparing the hypoglycemic agents of FormulaI. These novel intermediates have the formulae indicated below where Rand R₃₋₅ are as described above for Formula I: ##STR3##

It is to be understood that both the foregoing general and the followingdetailed description are exemplary and explanatory only and are notintended to be restrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain preferred embodiments ofthe invention; examples of which are illustrated below.

The hypoglycemic agents of Formula I can be prepared in accordance withthe reaction scheme described below. It should be noted that due to thepresence of basic nitrogen in the compounds of Formula I, acid additionthereto produces pharmaceutically acceptable salts which are included inthe scope of this invention. Methods of preparation of such salts arediscussed below, or are within the knowledge of those skilled in theart.

Guanidine derivative II, which is prepared as described in U.S. Pat. No.4,211,867, the entire disclosure of which is hereby incorporated hereinby reference, is treated with a suitable anhydride such as aceticanhydride and an appropriate base such as potassium carbonate in asuitable solvent such as methylene chloride at room temperature for 30minutes to 3 hours to give the amide derivative III. Compound III can betreated with a sulfur source such as Lawesson's reagent, in a suitablesolvent such as tetrahydrofuran (THF) at 0°-5° C. and stirred for 1-16hours to give the thioamide derivative IV. Alkylation of IV with asuitable alkylating agent such as methyl iodide and an appropriate basesuch as sodium hydride in a suitable solvent such as dimethylformamide(DMF) at 0° C. to room temperature for 1-16 hours gives the alkylatedderivative V. Compound V can be treated with an excess of a suitableamine in an appropriate solvent such as tetrahydrofuran (THF), at 0° C.to 100° C. for 1 hour to 30 days to give the substitutedcarboximidamides or guanidine derivatives I.

Alternatively, the amide derivative VI, can be treated with Meerwein'sReagent to give an imidate which is treated with guanidine derivative IIin an appropriate solvent, such as methylene chloride at roomtemperature to reflux for 1 hour to 12 days to give the substitutedcarboximidamides I. The amide derivative VI can be treated with phosgenein a suitable solvent such as toluene at 0° C. to reflux for 1-5 hours;followed by the addition of guanidine derivative II in a suitablesolvent such as methylene chloride and stirring at room temperature for5-16 hours to give the substituted carboximidamides I. Further,treatment of the amide derivative VI with dimethyl sulfate at 100° C.followed by the addition of the guanidine derivative II also gives thesubstituted carboximidamides I.

Treatment of a suitable nitrile derivative VII, such as isobutylnitrilewith an appropriate trialkyloxonium fluoroborate salt such astriethyloxonium tetrafluoroborate in a suitable solvent such asmethylene chloride at reflux for 4-6 hours gives the nitrilium saltderivative VIII. Treatment of said salt with guanidine derivative II atreflux for 16 hours gives the substituted carboximidamides I.

Therapeutically active non-toxic addition salts of carboximidamides I,were prepared by treatment of I with appropriate organic and inorganicacids such as hydrochloric, fumaric, saccharin, sulfuric, nitric,phosphoric, acetic, glycolic, pyruvic, mandelic, oxalic and the like ina suitable solvent. ##STR4##

As described above the compound of Formula II is known and is used as astarting material for producing the intermediate compounds of FormulaIII, IV and V.

The invention will now be illustrated by examples. The followingexamples describe the invention in greater particularity and areintended to be a way of illustrating but not limiting of the scope ofthe present invention. In conjunction with the detailed and generaldescription above, the examples provide further understanding of thepresent invention and outline a process for producing the compounds ofthe invention.

The following examples represent preferred embodiments of the compounds,compositions, processes and methods of the invention for satisfying thestated objects of the invention.

EXAMPLES

The following processes and procedures for preparing the compounds ofthe present invention are identified in the reaction schemes illustratedabove. The schemes and the specific examples below describe withparticularity the various chemical reactions and procedures utilized.Any methods, starting materials or reagents which are not particularlydescribed are those which are known to those skilled in the art.

Melting point determinations were carried out on a Thomas Hoovercapillary melting point apparatus and are uncorrected. All finalcompounds had spectra (elemental analysis) consistent with theirassigned structures. The elemental analysis were measured on a PerkinElmer 2400 spectrometer. All column chromatography were run using SilicaGel 60, 230-400 mesh and an appropriate commercially available solvent.Unless otherwise noted, the materials used in the examples were obtainedfrom readily available commercial suppliers or synthesized by standardmethods known to anyone skilled in the art of chemical synthesis. Thesubstituent groups, which vary between examples are assumed to behydrogen unless otherwise noted. The examples identified with a Cpd#correspond to those identified in the compound activity table (Table 5).

EXAMPLE 1 N-[4-Morpholinyl)(phenylimino)methyl]acetamide

A solution of acetic anhydride (4.4 mL, 45 mM) in methylene chloride (60mL) was added over 30 minutes to a stirred mixture of guanidinederivative II (NR₄ R₅ =morpholine 9.2 g, 45 mM, See U.S. Pat. No.4,211,867, and potassium carbonate (6.4 g, 45 mM) in methylene chloride(80 mL). The resulting mixture was stirred for 2.5 hours and washed withseveral portions of 15% NaOH (aq) solution. The combined aqueousextracts were saturated with NaCl and extracted several times withCHCl₃. The combined organic extracts were dried (K₂ CO₃), filtered, andconcentrated in vacuo to give the amide III (R=CH₃) as a solid: mp92°-95° C. Using the general procedure above but utilizing differentanhydrides the compounds listed in Table 1 were synthesized.

                  TABLE 1                                                         ______________________________________                                        R           mp (°C.)                                                   ______________________________________                                        n-C.sub.6 H.sub.11                                                                        69-76                                                             C.sub.2 H.sub.5                                                                           105-108                                                           i-C.sub.3 H.sub.7                                                                         Not Available (N.A.)                                              ______________________________________                                    

EXAMPLE 2 N-[(4-Morpholinyl)(phenylimino)methyl]ethanethioamide•HCl

Lawesson's reagent (16.48 g, 41.20 mM) was added to a stirred solutionof amide III (R=CH₃, NR₄ R₅ =morpholine: 18.57 g, 74.9 mM) in THF at0°-5° C. under N₂. The mixture was stirred for 3.5 hours at 0°-5° C. andfor 16 hours at room temperature. The resulting oil was dissolved inacetone (150 mL) and treated with ether/HCl. The thioamide IV wasisolated as its HCl salt from the treated oil as a solid, mp 181°-184°C.

The following general procedure was used in the synthesis of thecompounds listed in Table 2:

Lawesson's reagent (1 molar equivalent) was added to a stirred solutionof amide III (2 molar equivalents) in a suitable solvent at 0°-5° C.under N₂. The mixture was stirred for 3-5 hours at 0°-5° C. and for16-72 hours at room temperature. The resulting oil was purified by anyof the standard techniques which include chromatography andrecrystallization to give the thioamide derivative IV. HCl salts areobtained by treating the product compounds with HCl in an appropriatesolvent, e.g. ether.

                  TABLE 2                                                         ______________________________________                                        R                mp (°C.)                                              ______________________________________                                        n-C.sub.6 H.sub.11                                                                             oil                                                          C.sub.2 H.sub.5 (HCl Salt)                                                                     176-179                                                      i-C.sub.3 H.sub.7 (HCl Salt)                                                                   (N.A.)                                                       ______________________________________                                    

EXAMPLE 3N-[1-(Methylthio)ethylidene]-N'-phenyl-4-morpholinecarboximidamide

The HCl salt of thioamide IV (R=CH₃, NR₄ R₅ =morpholine: 17.94 g, 60 mM)was added to a suspension of hexane washed sodium hydride (50% oildispersion: 5.76 g, 120 mM) in THF (140 mL) at 0° C. under N₂. Theresulting mixture was stirred for 25 minutes at 0° C. and for 2 hours atroom temperature. Methyl iodide (3.72 mL, 60 mM) was added, and theresulting mixture was stirred for 2 hours at room temperature andconcentrated in vacuo. Aqueous NaOH (15%) and methylene chloride wereadded to the residue. The organic layer was washed with successiveportions of 15% NaOH (aq) and brine, dried (K₂ CO₃), filtered, andconcentrated in vacuo to give the thiomethyl derivative V (14.26 g, 86%)as an oil which crystallized upon standing.

The following general procedure was used in the synthesis of thecompounds listed in Table 3:

The thioamide derivative IV (1 molar equivalent) was added to asuspension of hexane washed sodium hydride (50% oil dispersion: 1-2molar equivalents) in THF at 0° C. under N₂. The resulting mixture wasstirred at 0° C. and at room temperature. Methyl iodide (1-4 molarequivalents) was added, and the resulting mixture was stirred at roomtemperature and concentrated in vacuo. Aqueous base and a suitableorganic solvent were added to the residue. The organic layer was washedwith successive portions of aqueous base and brine, dried (K₂ CO₃) andconcentrated in vacuo to give the thiomethyl derivative V, which wasused without further purification.

Table 3

C₆ H₁₁

C₂ H₅

i-C₃ H₇

EXAMPLE 4N-[1-(Piperidinyl)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-ButenedioateCpd 5

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 1.85 g, 6.67 mM) wasadded to a solution of piperidine (66 mL, 6.67 mM) in THF (70 mL) andthe mixture was stirred at room temperature for 48 hours and at refluxfor another 48 hours under N₂. The reaction mixture was concentrated invacuo, partitioned between methylene chloride and 15% NaOH (aq). Theresulting organic layer was dried (K₂ CO₃), concentrated in vacuo anddissolved in acetonitrile (10 mL). A solution of fumaric acid (0.69 g,5.9 mM) in isopropanol (20 mL) was added to the acetonitrile solutionfollowed by the addition of a portion of ether. The title compoundprecipitated out of this mixture as a solid: mp 154°-157° C.

Anal. Calc'd for C₁₈ H₂₆ N₄ O/C₄ H₄ O₄ : C, 61.38; H, 7.02; N, 13.01;Found: C, 61.19; H, 7.03; N, 12.96.

EXAMPLE 5N-[1-(Butylmethylamino)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-ButenedioateEthanolate (1:1:1) Cpd 9

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 2.65 g, 9.57 mM) wasadded to a solution of N-methyl-N-butylamine (8.34 g, 95.7 mM) in THF(20 mL) and was stirred at room temperature under N₂ for 84 hours. Thereaction mixture was concentrated in vacuo and partitioned betweenmethylene chloride and 15% NaOH (aq). The resulting organic layer wasdried (K₂ CO₃), and concentrated in vacuo. The residue was dissolved inether (30 mL), filtered through Decalite, and added to a solution offumaric acid in EtOH. The title compound precipitated as a solid: mp94°-99° C.

Anal. Calc'd for C₁₈ H₂₈ N₄ O/C₄ H₄ O₄ /C₂ H₆ O: C, 60.23; H, 8.00; N,11.71; Found: C, 60.16; H, 7.71; N, 12.05.

EXAMPLE 6N-[1(1-Methylethyl)amino]ethylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 10

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 4.71 g, 17.4 mM) wasadded to isopropylamine (30 mL, 353 mM) and stirred at room temperaturefor 16 hours and at 45° C. for another 84 hours in a pressure bottle.The reaction mixture was concentrated in vacuo, partitioned betweenmethylene chloride and 15% NaOH (aq). The resulting organic layer wasdried (K₂ CO₃), filtered, and concentrated in vacuo. The residue wastriturated with ether and followed by trituration with hexane. The titlecompound was isolated from this mixture as a white solid: mp 142°-145°C.

Anal. Calc'd for C₁₆ H₂₄ N₄ O: C, 66.64; H, 8.39; N, 19.43; Found: C,66.45; H, 8.40; N, 19.27.

EXAMPLE 7N-[1-(Morpholinyl)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-ButenedioateEthanolate (3:3:1) Cpd 19

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 1.40 g, 5.00 mM) wasadded to a solution of morpholine (10 mL, 115 mM) in THF (40 mL) and wasstirred at 60° C. for 72 hours under N₂. The reaction mixture wasconcentrated in vacuo and partitioned between methylene chloride and 15%NaOH (aq). The resulting organic layer was dried (K₂ CO₃), filtered, andconcentrated in vacuo. A solution of fumaric acid (0.69 g, 5.95 mM) inEtOH (20 mL) was added to a solution of the residue (1.93 g) in EtOH.The title compound precipitated out of this mixture as a solid: mp185°-187° C.

Anal. Calc'd for C₁₈ H₂₆ N₄ O/C₄ H₄ O₄ /0.33 C₂ H₆ O: C, 58.11; H, 6.75;N, 12.51; Found: C, 57.96; H, 6.79; N, 12.50.

EXAMPLE 8N'-Phenyl-N-[1-[(phenylmethyl)amino]ethylidene]-4-morpholinecarboximidamideCpd 22

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 1.51 g, 5.45 mM) wasadded to benzylamine (6.00 mL, 54.9 mM) and stirred at room temperaturefor six days under N₂. The resulting mixture was diluted with chloroformand washed several times with 3N HCl. The organic layer was extractedwith 3N NaOH (aq), dried (K₂ CO₃), filtered, concentrated and trituratedwith hexane. The title compound was isolated from the treated residue asa solid: mp 126°-129° C.

Anal. Calc'd for C₂₀ H₂₄ N₄ O: C, 71.40; H, 7.19; N, 16.65; Found: C,71.34; H, 7.21 N, 16.66.

EXAMPLE 9N'-Phenyl-N-[1-(n-propylamino)ethylidene]-4-morpholinecarboximidamideCpd 24

Thiomethyl derivative V (R=CH₃, NR₄ R₅ =morpholine: 2.00 g, 7.22 mM) wasadded to n-propylamine (20 mL, 243 mM) and stirred at room temperaturefor 72 hours. The resulting mixture was concentrated in vacuo andcrystallized from cyclohexane to give the title compound as a solid: mp101°-103° C.

Anal. Calc'd for C₁₆ H₂₄ N₄ O: C, 66.64; H, 8.39; N, 19.43; Found: C,66.71; H, 8.39; N, 19.40.

EXAMPLE 10N-[1-(Dimethylamino)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-Butenedioate(2:3) Cpd 3

Dimethylamine was bubbled into a solution of the thiomethyl derivative V(R=CH₃, NR₄ R₅ =morpholine: 2.77 g, 10.00 mM) in THF (200 mL) at roomtemperature for 15 minutes. The resulting mixture was stirred at roomtemperature for 16 hours, concentrated in vacuo, and partitioned betweenchloroform and 15% NaOH (aq). The resulting organic layer was dried (K₂CO₃), filtered, and concentrated in vacuo. The resulting oil wastriturated with Et₂ O to give a white solid. This solid was dissolved inEtOH and combined with a solution of furmaric acid with EtOH. The titlecompound precipitated as a solid: mp 150°-151° C.

Anal. Calc'd for C₁₅ H₂₂ N₄ O/(3/2):C₄ H₄ O₄ : C, 56.24.; H, 6.29; N,12.47; Found: C, 56.28; H, 6.36; N, 12.45.

The following general procedure was used to synthesize the compoundslisted in Table 4:

Dimethylamine was bubbled into a solution of the thiomethyl derivative Vin THF at 0° C. to room temperature for 10-30 minutes. The resultingmixture was stirred at room temperature for 16-72 hours concentrated invacuo, and partitioned between chloroform and 15% NaOH (aq). The organiclayer was dried (K₂ CO₃), filtered, concentrated in vacuo and dissolvedin a suitable solvent. A solution of fumaric acid in an appropriatesolvent was added to a solution of the residue in a suitable solvent.The desired carboximidamide I, precipitated as the solid fumaric salt.

                  TABLE 4                                                         ______________________________________                                                              Elemental                                                                     Analysis                                                R          R.sub.1                                                                              R.sub.2 mp °C.                                                                         C    H    N                                 ______________________________________                                        Cpd 4 C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             CH.sub.3                                                                            141-144 59.22                                                                              6.95 13.81                           Cpd 8 n-C.sub.6 H.sub.13                                                                     CH.sub.3                                                                             CH.sub.3                                                                              140-143.5                                                                           60.25                                                                              7.49 10.74                           ______________________________________                                    

EXAMPLE 11N-[1-(Ethylamino)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-ButenedioateCpd 30

Ethylamine was bubbled into a stirred solution of the thiomethylderivative V (R=CH₃, NR₄ R₅ =morpholine: 2.00 g, 7.22 mM) in THF (100mL) for 10 minutes twice over a 12 day period. The resulting mixture wasconcentrated in vacuo. A solution of fumaric acid in isopropanol wasadded to a solution of the residue in isopropanol. The title compoundprecipitated as a solid: mp 155.5°-158.5° C.

Anal. Calc'd for C₁₅ H₂₂ N₄ O/C₄ H₄ O₄ : C, 58.45; H, 6.71; N, 14.35;Found: C, 58.36; H, 6.76; N, 14.28.

EXAMPLE 12N-[1-[(1,1-Dimethylethyl)amino]ethylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 21

The thiomethylderivative V (R=CH₃, NR₄ R₅ =morpholine: 1.94 g, 7.00 mM)was dissolved in t-butylamine (100 mL), placed in a pressure bottle andheated from 60°-75° C. for 26 days. The resulting mixture wasconcentrated in vacuo and partitioned between CH₂ Cl₂ and water. Theorganic layer was dried (K₂ CO₃), filtered, and concentrated in vacuo.The treated residue was triturated with ether/cyclohexane andrecrystallized from ether to give the title compound as a solid: mp164°-166.5° C.

Anal. Calc'd for C₁₇ H₂₆ N₄ O: C, 67.52; H, 8.67; N, 18.53; Found: C,67.53; H, 8.67; N, 18.51.

EXAMPLE 13 N'-Phenyl-N-[1-[phenyl(phenylmethyl)amino]ethylidene]-4morpholinecarboximidamide Compound with 1,2-Benzisothiazol-3(2H)-one, 1,1 Dioxide Cpd 15

A solution of N-benzyl-N-phenylacetamide (JACS 1953, 75, 744: 17.94 g,79.73 mM) in methylene chloride (200 mL) was added to freshly preparedEt₃ O(+)BF₄ (-) (Organic Syntheses 1966, 46, 113-115: Et₂ OBF₃ 35.3 mM,epichlorohydrin 26.5 mM, ether 300 mL) at room temperature under Ar. Thereaction mixture was stirred at room temperature for 3 hours. A solutionof guanidine derivative II (NR₄ R₅ =morpholine: 16.35 g, 79.73 mM) inmethylene chloride (150 mL) was added to the reaction mixture andstirred at room temperature for 72 hours. The resulting mixture waswashed with successive portions of water and 15% NaOH (aq). The organiclayer was separated, dried (K₂ CO₃), filtered, and concentrated invacuo. A solution of saccharin in EtOH was added to an equimolar portionof the treated residue which was dissolved in EtOH. The title compoundprecipitated as a white solid: mp 170°-173° C.

Anal. Calc'd for C₂₆ H₂₈ N₄ O/C₇ H₅ NO₃ S: C, 66.54.; H, 5.58; N, 11.76;Found: C, 66.49; H, 5.73; N, 11.85.

EXAMPLE 14N'-Phenyl-N-[1-(phenylamino)ethylidene]-4-morpholinecarboximidamideCompound with 1,2-Benzisothiazol-3(2H)-one, 1,1 Dioxide Cpd 16

10% Palladium on carbon (1.95 g) and conc. HCl (3 mL) were added to asolution ofN'-phenyl-N-[1-[phenyl(phenylmethyl)amino]-ethylidene]-4-morpholinecarboximidamide(9.75 g, 23.56 mM) in EtOH (150 mL). The resulting mixture was placed ina Parr Bottle and pressurized with H₂ for 48 hours. The reaction mixturewas filtered through Decalite and concentrated in vacuo. The residue waspartitioned between water and methylene chloride. The organic extractwas washed with 15% NaOH (aq), dried (K₂ CO₃), filtered and concentratedin vacuo. The treated residue was dissolved in EtOH (10 mL) and added toa solution of saccharin (1.83 g) in EtOH (15 mL). The title compoundprecipitated out of this mixture as a solid: mp 180°-181.5° C.

Anal. Calc'd for C₁₉ H₂₂ N₄ O/C₇ H₅ NO₃ S: C, 61.77; H, 5.38; N, 13.85;Found: C, 61.69; H, 5.43; N, 13.83.

EXAMPLE 15 N-[1-Aminoethylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 23

A solution of acetamide (1.35 g, 22.55 mM) in methylene chloride (50 mL)was added to freshly prepared Et₃ O(+)BF4(-), (Et₂ OBF₃ 35.3 mM,epichlorohydrin 26.5 mM, ether 300 mL) at room temperature under Ar. Thereaction mixture was stirred at room temperature for 16 hours. Guanidinederivative II (NR₄ R₅ =morpholine: 4.62 g, 22.5 mM) was added to thereaction brew and stirred at room temperature for 72 hours. Theresulting mixture was washed with 15% NaOH (aq) and the organic layerwas separated, dried (K₂ CO₃), filtered, and concentrated in vacuo. Theresidue was purified by column chromatography using ammonium hydroxideand methanol as eluents followed by recrystallization of the desiredfractions from cyclohexane to give the title compound as a solid: mp146°-148° C.

Anal. Calc'd for C₁₃ H₁₈ N₄ O: C, 63.39; H, 7.37; N, 22.75; Found: C,63.23; H, 7.44; N, 22.66.

EXAMPLE 16N-[1-(2-Hydroxyethyl)aminoethylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 31

A solution of the amide derivative VI (R=CH₃, R₁ =--(CH₂)₂ OH: 3.36 g,22.5 mM) in methylene chloride (20 mL) was added to freshly prepared 1NEt₃ O(+)BF₄ (-)/methylene chloride (100 mL) at 0° C. under Ar. Thereaction mixture was warmed to room temperature and stirred for 16hours. Guanidine derivative II (NR₄ R₅ =morpholine: 4.62 g, 22.5 mM) wasadded to the reaction brew and the resulting mixture was stirred at roomtemperature for 16 hours and at 45° C. for an additional 6 days. Theresulting mixture was washed with 15% NaOH (aq). and the organic layerwas separated, dried (K₂ CO₃) and concentrated in vacuo. The residue waspurified by column chromatography using ammonium hydroxide and methanolas eluents followed by crystallization of the desired fractions fromether to give the title compound as a solid: mp 132°-134° C.

Anal. Calc'd for C₁₅ H₂₂ N₄ O₂ : C, 62.05; H, 7.64; N, 19.30; Found: C,62.06; H, 7.65; N, 19.26.

EXAMPLE 17N-[1-(Methylphenylamino)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-Butenedioate Hydrate (2:2:1) Cpd 11

N-Methyl-N-phenylacetamide (13.6 g, 90 mM) and dimethyl sulfate (8.4 mL,90 mM) were heated on a steam bath under N₂ until crystals began to forminside the reaction vessel. A solution of guanidine derivative II(R=CH₃, NR₄ R₅ =morpholine: 18.45 g, 90 mM) in methylene chloride (140mL) was added to the mixture and the resulting mixture was stirred atroom temperature for 1 hour. The reaction mixture was filtered and thefiltrate was partitioned between 3N HCl and ether. The aqueous layer wasextracted with several portions of chloroform and the combinedchloroform extracts were washed with 15% NaOH (aq), dried (K₂ CO₃),filtered and concentrated in vacuo. The residue was dissolved in ether(50 mL), filtered through Decalite, and added to a solution of fumaricacid (3.85 g) in EtOH (100 mL). The title compound precipitated as awhite solid: mp 160°-161.5° C.

Anal. Calc'd for C₂₀ H₂₄ N₄ O/C₄ H₄ O₄ /0.5H₂ O: C, 62.41; H, 6.34; N,12.13; Found: C, 62.49; H, 6.41; N, 12.10.

EXAMPLE 18N-[1-(Methylamino)ethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-Butenedioate (2:3) Cpd 7

Monomethylamine was bubbled into a solution of the thiomethyl derivativeV (R=CH₃, NR₄ R₅ =morpholine: 1.10 g, 3.99 mM) in THF (60 mL) for 15minutes and the resulting mixture was stirred at room temperature in astoppered flask for 24 hours. An additional portion of monomethylaminewas bubbled into the reaction mixture and the mixture was stirred foranother 24 hours. The resulting mixture was concentrated in vacuo andpartitioned between 15% NaOH (aq) and methylene chloride. The organiclayer was dried (K₂ CO₃), filtered, and concentrated in vacuo. Asolution of the residue in isopropanol was added to a solution offumaric acid in isopropanol. The title compound precipitated as a whitesolid: mp 145°-147° C.

Anal. Calc'd for C₁₄ H₂₀ N₄ O/C₄ H₄ O₄ (2:3): C, 55.29; H, 6.03; N,12.90; Found: C, 55.14; H, 6.05; N, 12.86.

EXAMPLE 19N-[1-(Dimethylamino)-2-methylpropylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 6

Dimethylamine was bubbled (15 minutes) into a solution of freshlyprepared alkylated thio derivative V (R=i-Pr, NR₄ R₅ =morpholine: 10 mM)in THF (70 mL). The resulting mixture was placed in a pressure bottle,heated from 50°-68° C. for five days and concentrated in vacuo. Thetreated residue was partitioned between 15% NaOH (aq) and chloroform,and the resulting organic layer was dried (K₂ CO₃), filtered, andconcentrated in vacuo. Crystallization of the residue from hexaneafforded the title compound as a solid: mp 88°-90° C.

Anal. Calc'd for C₁₇ H₂₆ N₄ O: C, 67.52; H, 8.67; N, 18.53; Found: C,67.54; H, 8.69; N, 18.51.

EXAMPLE 20N-[2-Methyl-1-(methylamino)propylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 13

Methylamine was bubbled (15 minutes) into a solution of freshly preparedalkylated thio derivative V (R=i-Pr, NR₄ R₅ =morpholine: 11.87 mM) inTHF (100 mL). The resulting mixture was stoppered and stirred at roomtemperature for 72 hours. Another portion of methylamine was bubbled (15minutes) into the reaction mixture and the resulting mixture was stirredfor another 48 hours. The mixture was concentrated in vacuo andpartitioned between 15% NaOH (aq) and methylene chloride. The organiclayer was dried (K₂ CO₃), filtered, and concentrated in vacuo. Thetreated residue was crystallized from ether to give the title compoundas a solid: mp 155°-157° C.

Anal. Calc'd for C₁₆ H₂₄ N₄ O: C, 66.64.; H, 8.39; N, 19.43; Found: C,66.52; H, 8.42; N, 19.37.

EXAMPLE 21N-[2-Methyl-1-[(1-methylethyl)amino]propylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 18

Freshly prepared alkylated thio derivative V (R=i-Pr, NR₄ R₅=morpholine: 1.20 g, 3.93 mM) was added to isopropylamine (100 mL); andthe mixture was stoppered and stirred at 62° C. for 16 hours. Theresulting mixture was concentrated in vacuo and partitioned between 15%NaOH (aq) and ether. The organic layer was dried (K₂ CO₃), filteredthrough Decalite and concentrated in vacuo. The residue wasrecrystallized from cyclohexane to give the title compound as a solid:mp 132°-135° C.

Anal. Calc'd for C₁₈ H₂₈ N₄ O: C, 68.32; H, 8.92; N, 17.71; Found: C,68.39; H, 9.01; N, 17.59.

EXAMPLE 22N-[1-(Ethylamino)-2-methylpropylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 26

Meerwein's reagent (1 molar in methylene chloride; 47.2 mL) was added toisobutylnitrile (1.7 g, 25 mM) and the resulting mixture was heated toreflux for 23 hours. Guanidine derivative II (NR₄ R₅ =morpholine: 2.5 g,12.2 mM) was added to the reaction and the resulting mixture was heatedat reflux for another 6 hours and stirred at room temperature overnight.The reaction was quenched with saturated NaHCO₃ and the resultingorganic layer was separated and washed with another portion of saturatedNaHCO₃. The organic phase was dried (MgSO₄), filtered and concentratedin vacuo. The residue was recrystallized from isopropanol and toluene.The resulting solid was partitioned between 3N NaOH and methylenechloride. The resulting organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo to give the title compound as a solid: mp155°-158° C.

Anal. Calc'd for C₁₇ H₂₆ N₄ O: C, 67.52; H, 8.67; N, 18.53; Found: C,66.32; H, 8.61; N, 18.20.

EXAMPLE 23N'-[4-Fluorophenyl]-N-[2-methyl-1-(methylamino)propylidene]-4-morpholinecarboximideCpd 28

Trimethyloxonium tetrafluoroborate (10.42 g, 70.4 mM) was added to asolution of isobutylnitrile (7.3 mL, 80.6 mM) in methylene chloride (55mL), and the resulting mixture was heated to reflux for 36 hours. Thisreaction mixture was added to a solution of the fluoro-guanidinederivative II (R₃ =4-F, NR₄ R₅ =morpholine: 14.28 g, 64.0 mM) inmethylene chloride (60 mL) at 0° C. The resulting mixture was stirred at0° C. for 5 minutes and at room temperature for 5 hours. The resultingprecipitate was filtered and washed several times with methylenechloride. The organic filtrates were combined, cooled to 0° C., basifiedwith 3N NaOH (aq) to a ph>9, dried (MgSO₄), filtered, and concentratedin vacuo. The treated residue was crystallized from methylene chlorideand hexane to give the title compound as a solid: mp 150°-152° C.

Anal. Calc'd for C₁₆ H₂₃ FN₄ O: C, 62.72; H, 7.57; N, 18.28; Found: C,62.71; H, 7.62; N, 18.24.

EXAMPLE 24N-[2-Methoxyphenyl]-N-[2-methyl-1-(methylamino)propylidene]-4-morpholinecarboximideCpd 33

The title compound was prepared as described in Example 23 starting withtrimethyloxonium tetrafluoroborate (13.19 g, 89.2 mM), isobutylnitrile(9.7 mL, 107 mM) and the 2-methoxy-guanidine derivative II (R₃ =2-OMe,NR₄ R₅ =morpholine, prepared using the methods outlined in U.S. Pat. No.4,211,867: 29.13 g, 80.2 mM) in methylene chloride to give a solid: mp149°-151° C.

Anal. Calc'd for C₁₇ H₂₆ N₄ O₂ : C, 64.12; H, 8.23; N, 17.59; Found: C,64.07; H, 8.25; N, 17.54.

EXAMPLE 25N-[2-Methyl-1-(propylamino)propylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 27

Meerwein's reagent (47.2 mM) dissolved in methylene chloride (100 mL)was added to N-(n-propyl)isobutyramide (J. Org. Chem 1986, 51(20),3839-48: 5.2 g, 40 mM), and the resulting mixture was stirred at roomtemperature for 5 hours. Guanidine derivative II (NR₄ R₅ =morpholine:8.2 g, 40 mM) was added to the reaction and the resulting mixture wasstirred at room temperature for 12 days. A solid precipitate was removedand the filtrate was washed with saturated NaHCO₃. The organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel using methanol/ammoniumhydroxide as an eluent and crystallized from hexane to give the titlecompound as a solid: mp 122.5°-123.5° C.

Anal. Calc'd for C₁₈ H₂₈ N₄ O: C, 68.32; H, 8.92; N, 17.71; Found: C,68.24; H, 8.93; N, 17.68.

EXAMPLE 26N-[1-Amino-2-methylpropylidene]-N'-phenyl-4-morpholinecarboximidamideCpd 25

Isobutyramide (3.92 g, 45 mM) was added to freshly prepared Et₃ O(+)BF₄(-) Et₂ OBF₃ 70.6 mM, epichlorohydrin 53 mM, ether 250 mL) at roomtemperature under Ar. The reaction mixture was stirred at roomtemperature for 16 hours. The reaction was quenched with 50% Na₂ CO₃ andfiltered. The organic layer was separated, dried (K₂ CO₃), concentratedin vacuo and distilled to give the imidate derivative as an oil. Thisimidate derivative was combined with the guanidine derivative II and THF(10 mL) (NR₄ R₅ =morpholine: 4.0 g, 19.48 mM) and stirred at roomtemperature for 16 hours and heated from 50°-80° C. for 4 days. Anotherportion of the imidate (4.78 g, 19.5 mM) was added to the reactionmixture and this mixture was heated at 50°-80° C. for 12 days. Theresulting mixture was concentrated in vacuo, and purified by acombination of column chromatography on silica gel usingmethanol/ammonium hydroxide as an eluent and sequentially crystallizedfrom diethyl ether and cyclohexane to give the title compound as a whitesolid: mp 123°-126° C.

Anal. Calc'd for C₁₅ H₂₂ N₄ O: C, 65.67; H, 8.08; N, 20.42; Found: C,65.54; H, 8.12; N, 20.35.

EXAMPLE 27N-[(Dimethylamino)methylene]-N'-phenyl-4-morpholinecarboximidamide Cpd 1

A solution of DMF (9 mL, 112.5 mM) in methylene chloride (75 mL) wasadded to freshly prepared Et₃ O(+)BF₄ (-) (Et₂ OBF₃ 176.0 mM,epichlorohydrin 132.0 mM, ether 500 mL) in methylene chloride (400 mL)at room temperature under Ar. The reaction mixture was stirred at roomtemperature for 6 hours. A solution of guanidine derivative II (NR₄ R₅=morpholine: 23.25 g, 112.5 mM) in methylene chloride (100 mL) was addedto the reaction brew and stirred at room temperature for 16 hours. Theresulting mixture was washed with successive portions of water and 15%NaOH (aq). The organic layer was separated, dried (K₂ CO₃), filtered,and concentrated in vacuo. The residue was purified by trituration withether to give the title compound as a white solid: mp 109°-112° C.

Anal. Calc'd for C₁₄ H₂₀ N₄ O: C, 64.59; H, 7.74; N, 21.52; Found: C,64.66; H, 7.78; N, 21.52.

EXAMPLE 28N-[(Dimethylamino)phenylmethylene]-N'-phenyl-4-morpholinecarboximidamideHydrochloride Cpd 2

Phosgene (2M in toluene: 50 mL) was added to a solution ofN'N-dimethylbenzamide (3.4 g, 22.5 mM) and the mixture was heated toreflux for 15 minutes. Another portion of phosgene (20 mL) was added andthe resulting mixture was heated to reflux for 50 minutes andconcentrated in vacuo. The guanidine derivative II (NR₄ R₅ =morpholine:4.65 g, 22.5 mM) in methylene chloride (40 mL) was added to a solutionof the residue in methylene chloride (30 mL) and the reaction wasstirred overnight at room temperature. The resulting mixture was washedwith water and the resulting aqueous layer was washed with severalportions of chloroform. The combined chloroform extracts wereconcentrated in vacuo and crystallized from ether to give the titlecompound as a solid: mp 215°-218° C.

Anal. Calc'd for C₁₄ H₂₀ N₄ O/HCl: C, 64.42; H, 6.76; N, 15.02; Found:C, 64.17; H, 6.84; N, 14.99.

EXAMPLE 29N-[1-(Dimethylamino)-2-phenylethylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-Butenedioate(1:1) Cpd 14

A solution of N,N-dimethylphenylacetamide (European Patent No.86-112499, Sep. 10, 1986: 11.93 g, 73.19 mM) in methylene chloride (150mL) was added to freshly prepared Et₃ O(+)BF₄ (-)(Et₂ OBF₃ 114.52 mM,epichlorohydrin 86.11 mM, ether 250 mL) at room temperature under Ar.The reaction mixture was stirred at room temperature for 3 hours. Asolution of guanidine derivative II (NR₄ R₅ =morpholine: 15.00 g, 73.19mM) in methylene chloride (150 mL) was added to the reaction brew andstirred at room temperature for 16 hours. The resulting mixture waswashed with successive portions of 3N HCl followed by successiveportions of 15% NaOH (aq). The resulting organic layer was dried (K₂CO₃), filtered, and concentrated in vacuo. A solution of fumaric acid(5.98 g, 51.51 mM) in EtOH (50 mL) was added to a solution of theresidue in EtOH (50 mL). The title compound precipitated as a solid: mp169.5°-171° C.

Anal. Calc'd for C₂₁ H₂₆ N₄ O/C₄ H₄ O₄ : C, 64.36; H, 6.48; N, 12.01;Found: C, 64.27; H, 6.54; N, 11.98.

EXAMPLE 30N-[1-(Dimethylamino)-2,2-dimethylpropylidene]-N'-phenyl-4-morpholinecarboximidamideCompound with 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide Cpd 17

A solution of N,N-dimethyltrimethylacetamide (J. Org. Chem. 1981, 46,1597-602: 2.90 g, 22.5 mM) in methylene chloride (60 mL) was added tofreshly prepared Et₃ O(+)BF₄ (-)(Et₂ OBF₃ 35.3 mM, epichlorohydrin 26.5mM, ether 75 mL) at room temperature under Ar. The reaction mixture wasstirred at room temperature for 4 hours. A solution of guanidinederivative II (NR₄ R₅ =morpholine: 4.65 g, 22.5 mM) in methylenechloride (30 mL) was added to the reaction brew and the resultingmixture was stirred at room temperature for 16 hours and concentrated invacuo. The residue was partitioned between water and ether and theresulting aqueous phase was washed with several portions of methylenechloride. The combined methylene chloride layers were washed withsuccessive portions of water, 3N HCl and 15% NaOH (aq), dried (K₂ CO₃),filtered, and concentrated in vacuo. A solution of saccharin (0.51 g) inEtOH (20-30 mL) was added to a filtered solution of the residue inether. The title compound precipitated out of this mixture as a whitesolid: mp 131.5°-133.5° C.

Anal. Calc'd for C₁₈ H₂₈ N₄ O/C₇ H₅ NO₃ S: C, 60.10; H, 6.66; N, 14.02;Found: C, 60.12; H, 6.69; N, 13.95.

EXAMPLE 31N-[1-Dimethylamino-3,3-dimethylbutylidene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-butenedioate(2:3) Cpd 20

A solution of N,N-dimethyl-tert-butylacetamide (J. Org. Chem. 1970, 35,1597-1602: 2.90 g, 22.5 mM) in methylene chloride (50 mL) was added tofreshly prepared Et₃ O(+)BF₄ (-)(Et₂ OBF₃ 35.3 mM, epichlorohydrin 26.5mM, ether 100 mL) at room temperature under Ar. The reaction mixture wasstirred at room temperature for 3 hours. A solution of guanidinederivative II (NR₄ R₅ =morpholine: 4.65 g, 22.5 mM) in methylenechloride (50 mL) was added to the reaction brew and stirred at roomtemperature for 72 hours. The mixture was concentrated in vacuo,partitioned between water and ether and the resulting solid wasfiltered. The solid was partitioned between 15% NaOH (aq) and methylenechloride. The organic layer was dried (K₂ CO₃), filtered, andconcentrated in vacuo. A solution of the residue (2.96 g) in EtOH (10mL) was added to a solution of fumaric acid (1.04 g) in EtOH (15 mL).The title compound precipitated out of this mixture as a solid: mp150°-152° C.

Anal. Calc'd for C₁₉ H₃₀ N₄ O/1.5 C₄ H₄ O₄ : C, 59.51; H, 7.19; N,11.10; Found: C, 59.43; H, 7.15; N, 11.05.

EXAMPLE 32N-[1-[[(4-Morpholinyl)(phenylimino)methyl]imino]ethyl]acetamide Cpd 32

Guanidine derivative II (NR₄ R₅ =morpholine: 5.12 g, 25 mM) andN-acetylacetimidic acid ethyl ester (Chem Ber, 1985, 118, 3089-3104:12.9 g, 100 mM) were stirred together at room temperature for 4 days.The resulting solid precipitate was separated and triturated withether/cyclohexane to give the title compound as a solid: mp 146°-149° C.

Anal. Calc'd for C₁₅ H₂₀ N₄ O₂ : C, 62.48; H, 6.99; N, 19.43; Found: C,62.43; H, 7.01; N, 19.39.

EXAMPLE 33N-[Cyclohexyl(dimethylamino)methylene]-N'-phenyl-4-morpholinecarboximidamide(E)-2-Butenedioate (2:3) Cpd 12

A solution of N,N-dimethylcyclohexylacetamide (U.S. Pat. No. 4,835,312,May 30, 1989: 11.32 g, 73 mM) in methylene chloride (150 mL) was addedto freshly prepared Et₃ O(+)BF₄ (-)(Et₂ OBF₃ 114.5 mM, epichlorohydrin85.9 mM, ether 200 mL) at room temperature under Ar. The reactionmixture was stirred at room temperature for 5 hours. A solution ofguanidine derivative II (NR₄ R₅ =morpholine: 14.97 g, 73 mM) inmethylene chloride (120 mL) was added to the reaction brew and stirredat room temperature for 72 hours. The resulting mixture was concentratedin vacuo and partitioned between water and ether. The aqueous phase wasextracted with several portions of ether followed by several portions ofmethylene chloride. The combined methylene chloride layers were washedwith successive portions of water and 15% NaOH (aq), dried (K₂ CO₃),filtered, and concentrated in vacuo. The residue was dissolved in EtOH(40 mL), added to a solution of fumaric acid (4.01 g) in EtOH (50 mL).The title compound precipitated out of this solution as a solid: mp169°-170.5° C.

Anal. Calc'd for C₂₀ H₃₀ N₄ O/(3/2)C₄ H₄ O₄ : C, 60.45; H, 7.02; N,10.85; Found: C, 60.60; H, 7.17; N, 10.83.

EXAMPLE 34N-[1-(Methylamino)propylidene]-N'-phenyl-4-morpholinecarboximidamide Cpd29

Monomethylamine was bubbled into a solution of thiomethyl derivative V(R=Et,NR₄ R₅ =morpholine: 3.47 g, 11.92 mM) in THF (100 mL) for 15minutes and the resulting mixture was stirred at room temperature in astoppered flask for 3 days. The resulting mixture was concentrated invacuo and partitioned between 15% NaOH (aq) and methylene chloride. Theorganic layer was dried (K₂ CO₃), filtered, and concentrated in vacuo.The residue was crystallized from cyclohexane to give the title compoundas a white solid: mp 117°-120° C.

Anal. Calc'd for C₁₅ H₂₂ N₄ O: C, 65.67; H, 8.08; N, 20.42; Found: C,65.70; H, 8.11; N, 20.26.

EXAMPLE 35 Compound Activity Evaluation

The compounds listed in Table 5 were tested for activity in a rat oralglucose tolerance test. Male Sprague-Dawley rats (200-275 grams) aregiven water ad libitum and fasted 18-24 hours prior to the experiment.Three to five rats are randomly assigned to each test and control group.Test compounds (2.5, 5.0, 10.0 mg/kg) are administered subcutaneously(0.5 mL) at 30 minutes prior to a standard oral glucose load (1 g/kgbody weight). Control animals are given an equal amount of vehicle (H₂ Oor 0.5% hydroxypropyl methyl cellulose). Drug doses are calculated asthe free base. Serial blood samples (0.1 milliliter) are obtained fromthe tail without anesthesia prior to (0 min) and at 30, 60, 90, 120, 150and 180 minutes after glucose administration. Blood samples areimmediately deproteinized with aqueous solutions of Ba(OH)₂ and ZnSO₄.and glucose concentrations in the supernatants are determined using theglucose oxidase assay described by L. P. Cawley et al., "Ultra MicroChemical Analysis of Blood Glucose with Glucose Oxidase", Amer. J. Clin.Path., 32, 195 (1959). The blood glucose values at each time point areexpressed in terms of milligram percent (mg glucose/100 mL of blood).The mean glucose values of the controls are compared statistically bythe unpaired Student's t-test to the means of the experimental group ateach corresponding time point. If the compound lowers the blood glucosesignificantly at any time at a 95% confidence limit, the compound isconsidered to have hypoglycemic activity. The maximum % lowering ofblood glucose from the corresponding mean values of the control group isdetermined for each rat in the experimental groups and used to calculatethe mean maximum percent lowering of glucose from control. The ED 30(dose producing a 30% decrease from control) and the 95% confidenceintervals (CI) are determined from regression analysis of the meanmaximum percent decrease from control vs log dose(mg/kg).

                                      TABLE 5                                     __________________________________________________________________________     ##STR5##                                                                     Cpd #                                                                             R    R.sub.1                                                                              R.sub.2                                                                              R.sub.3                                                                           Mean Max % Low                                                                          ED.sub.30 (95% CI)                       __________________________________________________________________________     1  H    CH.sub.3                                                                             CH.sub.3                                                                             H   22        ND                                        2  Ph   CH.sub.3                                                                             CH.sub.3                                                                             H   25        ND                                        3  CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.3                                                                             H   38        6.7 (5.2-10.1)                            4  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                             CH.sub.3                                                                             H   43        5.3 (3.3-9.1                              5  CH.sub.3                                                                           (CH.sub.2).sub.2                                                                     (CH.sub.2).sub.3                                                                     H   46        5.3 (3.0-9.2)                             6  i-Pr CH.sub.3                                                                             CH.sub.3                                                                             H   43        4.3 (3.0-5.6)                             7  CH.sub.3                                                                           H      CH.sub.3                                                                             H   45        2.6 (1.3-3.5)                             8  n-hexyl                                                                            CH.sub.3                                                                             CH.sub.3                                                                             H   31        ND                                        9  CH.sub.3                                                                           CH.sub.3                                                                             n-Bu   H   33        7.6 (5.2-20.8)                           10  CH.sub.3                                                                           H      i-Pr   H   42        3.9 (1.5-6.2)                            11  CH.sub.3                                                                           CH.sub.3                                                                             Ph     H   20        ND                                       12  c-hexyl                                                                            CH.sub.3                                                                             CH.sub.3                                                                             H   27        ND                                       13  i-Pr H      CH.sub.3                                                                             H   52        1.5 (1.1-1.9)                            14  Bzl  CH.sub.3                                                                             CH.sub.3                                                                             H   27        ND                                       15  CH.sub.3                                                                           Bzl    Ph     H   17        ND                                       16  CH.sub.3                                                                           H      Ph     H   26        ND                                       17  t-Bu CH.sub.3                                                                             CH.sub.3                                                                             H   40        9.6 (6.5-32)                             18  i-Pr H      i-Pr   H   23        ND                                       19  CH.sub.3                                                                           (CH.sub.2).sub.2 O                                                                   (CH.sub.2).sub.2                                                                     H   24        ND                                       20  CH.sub.2 -t-Bu                                                                     CH.sub.3                                                                             CH.sub.3                                                                             H   37        5.9 (3-36)                               21  CH.sub.3                                                                           H      t-Bu   H   45        4.2 (1.9-6.6)                            22  CH.sub.3                                                                           H      Bzl    H   50        4.3 (2.3-6.4)                            23  CH.sub.3                                                                           H      H      H   21        ND                                       24  CH.sub.3                                                                           H      n-Pr   H   56        0.97 (0.06-1.9)                          25  i-Pr H      H      H   34        ND                                       26  i-Pr Et     H      H   26        ND                                       27  i-Pr n-Pr   H      H   31        ND                                       28  i-Pr CH.sub.3                                                                             H      F   42        ND                                       29  Et   CH.sub.3                                                                             H      H   42        ND                                       30  CH.sub.3                                                                           Et     H      H   48        4.6 (3.8-5.3)                            31  CH.sub.3                                                                           (CH.sub.2).sub.2 OH                                                                  H      H   15        ND                                       32  CH.sub.3                                                                           C(O)CH.sub.3                                                                         H      H   22        ND                                       33  i-Pr CH.sub.3                                                                             H      OCH.sub.3                                                                         21        ND                                       Comparative compound: Linogliride                                                                        34        6.1 (4.3-8.1)                            __________________________________________________________________________     For Cpds. 5 and 19 R.sub.1 and R.sub.2 are taken together to form an          NR.sub.1 R.sub.2 heterocyclic ring.                                           Mean maximum % lowering is calculated as described in Example 35. The         values reported are determined at a dose of 10 mg/kg.                         ED.sub.30 equals the dose calculated to produce a 30% decrease of glucose     from control. The 95% confidence interval (CI) is shown in parentheses.       ND = Not Determined.                                                     

The above test results demonstrate the utility of the compounds of theinvention for decreasing the blood level of glucose in mammals (e.g.rats) thus demonstrating hypogylcemic activity.

Pharmaceutical compositions containing compounds of the invention maycomprise the compound of the present invention and a pharmaceuticallyacceptable carrier in either solid or liquid form. Solid formpreparations include powders, tablets, dispersible granules, capsules,etc. The carrier may also be one or more substances which act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents as well as encapsulatingmaterials. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carbosyl methyl cellulose, and the like. Liquid formpreparations include solutions which are suitable for oral or parenteraladministration, or suspensions and emulsions suitable for oraladministration.

Sterile water solutions of the active component or sterile solutions ofthe active components in solvents comprising water, ethanol, orpropylene glycol are examples of liquid preparations suitable forparenteral administration. Sterile solutions may be prepared bydissolving the active component in the desired solvent system, thenpassing the resulting solution through a membrane filter to sterilizeit, or alternatively, by dissolving the sterile compound in a previouslysterilized solvent under sterile conditions. Aqueous solutions for oraladministration can be prepared by dissolving the active compound inwater and adding suitable flavorants, coloring agents, stabilizers andthickening agents as required. Aqueous suspensions for oral use can bemade by dispersing the finely divided active component in water togetherwith a viscous material such as a natural or synthetic gum, methylcellulose, sodium carboxy methyl cellulose, and other suspending agentsknown to the pharmaceutical formulation art.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. The term "unit dosage form" asused herein refers to physically discrete units suitable as unitdosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier.

Various conventional techniques for preparing pharmaceuticalcompositions including solutions, suspensions, tablets or caplets can beemployed, as would be known to those skilled in the art and as isdisclosed for example by Remington's Pharmaceutical Sciences, MackPublishing Co., Part 8 Chapters 76-93, "Pharmaceutical Preparations andTheir Manufacture", pp. 1409-1677 (1985).

In thereapeutic use as hyperglycemic agents, the compounds utilized inthe methods of this invention may be administered to a patientpreferably orally (for those compounds which are orally active) oralternatively parenterally or subcutaneously, at effective dosage levelsof from about 30-1000 mg per day and preferably about 50-800 mg per day.The dosages, however, may be varied depending upon the results ofspecific clinical testing, the requirements of the patient, the weightand age of the patient, the severity of the condition being treated, andthe compound being employed. Determination of optimum dosages for aparticular situation is within the skill of the art.

The scope of the present invention is not limited by the description,examples and suggested uses described herein and modifications can bewithout departing from the spirit of the invention. For example,additional medicaments or active components may be used in combinationwith the compounds of the invention. Further, the novel intermediate andhypoglycemic active compounds of the invention may have other uses inaddition to those described herein. For example, the compounds of theinvention may be useful for treatment of cardiovascular disease states.

Applications of the compounds, compositions and methods of the presentinvention for medical or pharmaceutical uses can be accomplished by anyclinical, medical, and pharmaceutical methods and techniques as arepresently or prospectively known to those skilled in the art. Thus it isintended that the present invention cover any modifications andvariations of this invention provided that they come within the scope ofthe appended claims and their equivalents.

What is claimed is:
 1. A compound selected from the group consisting ofthe formulae: ##STR6## wherein: R is selected from the group consistingof H, alkyl (C₁ -C₈), branched alkyl (C₃ -C₅), cycloalkyl (C₃ -C₇), aryland aralkyl wherein the aryl portion is phenyl or naphthyl and the alkylportion is C₁ -C₅ ;R₃ is selected from the group consisting of alkyl (C₁-C₅), alkoxy (C₁ -C₄) and halogen; and R₄ and R₅ are independentlyselected from the group consisting of alkyl (C₁ -C₅), branched alkyl (C₃-C₅), cyclohexyl, cyclopentyl or R₄ R₅ N may be taken together to form aheterocyclic ring containing 3-5 carbon atoms or said ring additionallycontains one or more heteroatoms such as O, or S to form a heterocyclicring selected from the group consisting of piperidino, morpholino,pyrrolidino and thiamorpholino; and pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1 of the formula: ##STR7## 3.A compound according to claim 1 of the formula: ##STR8##